Effective: June 9, 2016 Supercedes: None CARBOWAX SENTRY Polyethylene Glycol (PEG) and Methoxypolyethylene Glycol (MPEG) Products Elemental Impurities / Metal Impurities USP general chapter <232> Elemental impurities Limits and USP <233> Elemental Impurities Procedure are expected to become effective on January 1, 2018. ICH Q3D Guideline: Impurities: Guideline for Metal Impurities was published as an EMA guideline in early 2014 (EMA/CHMP/ICH/353369/2013) with implementation dates of June 2016 for new marketing authorization applications and December 2017 for all existing products on EU market. The revised European Pharmacopoeia chapter 5.20 is a verbatim reproduction of ICH Q3D with the same implementation dates. This letter is intended to provide elemental impurity data for CARBOWAX PEG and MPEG Products as per USP <232> and ICHQ3D. Dow currently performs the following elemental testing on CARBOWAX PEG and MPEG Products: Heavy metals as per the USP test method to demonstrate compliance with the USP and Ph Eur. The USP heavy metals test will give positive indication for the presence of Ag, As, Bi, Cd, Hg, Mo, Pb, Sb, and Sn. In anticipation of customer requests for Elemental Impurity data as per USP <232> and ICH Q3D, Dow has completed an assessment of the manufacturing process and tested representative samples of CARBOWAX SENTRY PEG and MPEG Products. Conclusions of the manufacturing process assessment are as follows: Elemental impurities are not intentionally added to these products. Metal catalysts or reagents are not used in the CARBOWAX SENTRY PEG and MPEG manufacturing process. Dow has well-defined manufacturing processes and controls for CARBOWAX SENTRY PEG and MPEG production. Analytical results for USP <232> and ICH Q3D elemental impurities are summarized in Table I. All Class 1 and Class 2A elements were tested. Selenium and Cobalt were added to the USP list for testing due to the scheme in ICH Q3D. No Class 2B elements are intentionally added to the list, but some were tested due to the USP <232> requirements. Chromium and nickel are components of stainless steel. These trace impurities are from the materials of construction. In conclusion, based on the product chemistry, raw materials, materials of construction and the manufacturing processes and controls, as well as results of recent screening tests, CARBOWAX SENTRY PEG and MPEG products do not contain the majority of elemental impurities listed below. If you have any questions or require further information, please contact us via our web site at http://www.dow.com/polyglycols/. (Answer Center, Ask a Question tab).
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Table I Elemental Impurity Class Likely to be Present Concentration /Units (ppm) ND = Not Detected Analytical Method Used (and Limit of Detection if Available) Comments regarding source of information (i.e.; frequency of testing, process understanding, etc.) Arsenic (inorganic) As 1 Yes No Unknown ND Cadmium Cd 1 Yes No Unknown ND Mercury (inorganic) Hg 1 Yes No Unknown ND Lead Pb 1 Yes No Unknown ND Cobalt Co 2A Yes No Unknown ND Nickel Ni 2A Yes No Unknown ND Samples tested (1, 3) Components of stainless steel Vanadium V 2A Yes No Unknown ND Samples tested (1, 3) Silver Ag 2B Yes No Unknown Not tested Gold Au 2B Yes No Unknown ND Iridium Ir 2B Yes No Unknown ND Osmium Os 2B Yes No Unknown ND
Elemental Impurity Class Likely to be Present Concentration /Units (ppm) ND = Not Detected Palladium Pd 2B Yes No Unknown ND Platinum Pt 2B Yes No Unknown ND Rhodium Rh 2B Yes No Unknown ND Ruthenium Ru 2B Yes No Unknown ND Selenium Se 2B Yes No Unknown ND Thallium Tl 2B Yes No Unknown ND Barium Ba 3 Yes No Unknown ND Chromium Cr 3 Yes No Unknown ND Copper Cu 3 Yes No Unknown ND Lithium Li 3 Yes No Unknown ND Molybdenum Mo 3 Yes No Unknown ND Antimony Sb 3 Yes No Unknown ND Tin Sn 3 Yes No Unknown ND Analytical Method Used (and Limit of Detection if Available) (LOD 1 ppm) Comments regarding source of information (i.e.; frequency of testing, process understanding, etc.) Components of stainless steel Samples tested (1, 2) Aluminum Al 4 Yes No Unknown ND Not tested
1) The PEG samples were prepared by diluting the solids by a total factor of 100 in 2% HCl. The prepared solutions were analyzed using inductively coupled plasma-mass spectrometry (ICP-MS). The instrument was calibrated over the range of 0 10 ng/ml using 0.5, 1.0, 5.0 and 10.0 ng/ml calibration standards made up in 1% HCl. The results obtained were based on the dilution factor, mass of samples taken and the final volume of the solution. The estimated error of the analysis is ± 10%. 2) The PEG samples were analyzed by Neutron Activation Analysis (NAA). Samples were prepared and irradiated for 30 minutes at 250 kw of reactor powder. After a waiting time, the gamma spectroscopy was completed. 3) The PEG samples were prepared by diluting the solids by a total factor of 100 in 1% HCl. The prepared solutions were analyzed using inductively coupled plasma-mass spectrometry (ICP-MS). The instrument was calibrated over the range of 0 10 ng/ml using 0.5, 1.0, 5.0 and 10.0 ng/ml calibration standards made up in 1% HCl. The results obtained were based on the dilution factor, mass of samples taken and the final volume of the solution. The estimated error of the analysis is ± 10%.